1. Field of the Invention
This invention provides novel synthetic peptide derivatives and the salts thereof with pharmacological activity. The synthetic peptide derivatives and the salts thereof of this invention show bone morphogenetic protein antagonist like activity. This invention with bone morphogenetic protein antagonist activity is useful for treating and preventing bone metabolic diseases accompanied by ectopic calcification, ectopic bone formation or calcification, such as neural osteosis, ectopic ossification by postoperative stress, traumatic ossific myositis, ossification by oxygen supply deficit, osteogenic tumor, ligamentum longitudinale postreius osteosis (OPLL) and arterial sclerosis.
Bone morphogenetic protein (BMP) is a protein with bone morphogenetic activity in decalcified bone tissue. Although the isolation of BMP had been worked on energetically since the 1970s, it did not succeeded in isolating as a single protein. Gene cloning of BMP was performed by Wozney in 1989 by molecular biological method, using the amino acid sequences derived from unknown peptides which were separated from treating the fraction having BMP activities with an enzyme. The gene was immediately introduced to the animal cultured cells, and the activity of the protein expressed was measured in vivo, and BMP activity in the protein was proved (Wang, E. A. et al., (1990) Proc. Natl. Acad. Sci. USA, vol.87, p.2220-2224). Continuing the protein cloning of similar activities utilizing homology, several numbers of the proteins, that is from BMP-2 to BMP-9 have been identified so far. Those proteins belong to TGF-.beta. gene super family and are confirmed to have the activity to cause ectopic ossification in vivo, basically. Ossification caused by BMP is said to be internal cartilaginous and it seems to reproduce the formation of long bone at an embryonal stage. Therefore, BMP itself can be used as a medical agent for the treatment to compensate the bone deficit.
2. Description of the Prior Art
On the other hand, since BMP genes were reported, the specific antibodies against BMP were prepared and BMPs were also existed in critical parts of ectopic calcification, ectopic ossification and so on, which have not had any treatment so far, there seem some possibilities of the relationship between BMPs and those diseases. Recently it is evident that BMP is existed or included in diseases such as neural osteosis, ectopic ossification by postoperative stress, traumatic ossific myositis, ossification by oxygen supply deficit, osteogenic tumor, specified as refractory diseases such as ossification of the posterior longitudinal ligament (OPLL) (Spine, 17-3S, S33, 1992) and calcification part of arterial sclerosis (J. Clin. Invest., vol. 91, p.1800, 1993). In addition, the major symptoms of pseudomalignant heterotopic ossification (PHO), pseudomalignant osseous tumor, myosistis ossificans circumscripta are ache and the existence of the mass in hard tissue of the muscle. Though the causes of these diseases are still unknown in detail, BMP seems to have a relation to the existence in hard tissue of the muscle of the patients. It is considered that BMP existed in the tissue which is not supposed to exist, acts on autocrine and bone like hard tissue is formed.
There is no effective treatment for OPLL by now. If the oppressive neural symptom is serious, excision is occurred. However prognosis is not so good. There is no treatment for calcification of artery, either. It seems that suppression of BMP existence may be one of the major treatments for these diseases. Another treatment, such as administration of BMP antagonists, also seems effective.
Therefore, it was desired eagerly the effective method of treatment for above described diseases related to bone like tissue formation. BMP receptors, neutralized antibodies against BMP and the peptide according to BMP's binding position are thought to have BMP antagonist like activity.